Mood disturbances which may require clinical attention affect more than 10% of the adult population during their lifetime, and the occurrence of bipolar disorders (manic-depressive illness) is estimated as high as 5% in the general population (Merck Index, 1999). A main therapy for the mood disorders comprises delivering lithium salts (Li); however, Li has a narrow therapeutic window and exhibits toxic effects, requiring careful blood monitoring. Besides, Li at therapeutic levels exhibits adverse effects, including gross tremor, persistent headache, vomiting, mental confusion, and possibly cardiac arrhythmias and various chronic problems, and 30% of the patients do not respond to the treatment. At certain stages and for some cases, anticonvulsants and antipsychotics are also used in treating bipolar disorders, but they may be teratogenic, and 30% of the patients do not respond. Therefore, an urgent need is felt for new drugs.
The mechanism of the therapeutic effect of Li is still unknown despite numerous reported biochemical effects. Inositol monophosphatase (IMPase) remains a viable target [Harwood and Agam, 2003, Ohnishi et al., 2007]. IMPase has an important role in the phosphatidylinositol (PI) signaling system since it catalyzes the dephosphorylation of myo-inositol monophosphates to free myo-inositol. It was shown that therapeutically-relevant lithium concentrations (0.5-1.5 mM) exert an uncompetitive inhibition on IMPase with a Ki of 0.8 mM, probably by binding to the Mg2+-binding sites of the enzyme [Hallcher and Sherman, 1980]. Reduced activity of IMPase may lead to depletion of intracellular free myo-inositol, which is used in the re-synthesis of the signalling precursor PI. Based on this, several pharmaceutical companies have tried to synthesize IMPase inhibitors targeting the substrate site of the enzyme, such as terpenoid and tropolone analogues [Fauroux and Freeman, 1999], and bisphosphonates, but their development to clinical mood stabilizers was limited for a variety of reasons. [Atack, 1997]. It is therefore an object of this invention to provide a new system for reducing the activity of IMPase.
It is another object of this invention to reduce IMPase without the use of Li.
It is still another object of this invention to positively affect mood disorders without the drawbacks of prior art methods.
Other objects and advantages of present invention will appear as description proceeds.